Presentation Speech by Professor Georg Klein
Karolinska Medico-Chirurgical Institute
Translation from the Swedish text
Your Majesty, Your Royal Highnesses, Ladies
Even the longest journey starts with a single step, the old Chinese have said. The first step of the long journey that has led the three Laureates in Medicine to us tonight was taken in regions that were far from each other. None of the three knew that they were on their way towards the same chromosome, or, more precisely, the same gene region within one chromosome, now known to influence immune functions in various ways. It is a large region, it can be called a supergene. The system is very ancient: all vertebrates have it: thus, it has been highly conserved during evolution. Its stability across species barriers is in remarkable contrast to its many thousandfold variability within each species, giving rise to a kaleidoscopic pattern that makes all human beings individually distinct, with identical twins as the only exception.
Where did the journey start? George Snell became interested in the genetics of cancer during the 1930s. At that time, the Jackson Laboratory in Bar Harbor, Maine had just succeeded to produce the first highly inbred strains of mice, after more than a decade of brother-sister mating. Within each strain, every mouse had the same genetic constitution, like identical twins. Experiments were performed on the role of genetic factors for the development of cancer. In the same context, tumor cells were also transplanted from cancerous to healthy mice. Snell found that transplanted tumors grew progressively in all mice of the same strain, but were rejected in foreign strains. Crossing experiments showed that transplanted tumor cells could only grow if the donor and the recipient shared certain dominant genes. In the absence of such identity, the tumor cells were killed by a host cell, called the killer lymphocyte. Snell realized at an early stage that the reaction was not limited to cancer cells: the transplantability of normal tissues was regulated by the same genes. Snell called them "histocompatibility genes" or H-genes. The mouse has at least 80 different H-genes. All of them are not equally important. Some give stronger reactions than others. The strongest gene that played the most important role for rejection was called H-2. Even the most highly malignant tumor cell cannot escape the rejection reaction induced by a foreign H-2 component, as a rule.
The analysis of the H-2 system by Snell became a monumental masterpiece in mammalian genetics that has laid the foundations of a new science: transplantation immunology and immunogenetics.
At the time when Dausset started his activities in this field, it was already clear that humans reject foreign grafts by the same type of immune mechanism as mice. Since human beings cannot be studied experimentally, nor are they inbred, it was thought that it will take many decades before human H-genes will be identified and mapped. Dausset worked on something quite different. He found that patients who received many blood transfusions produced antibodies that killed white blood cells. At first, he thought that this was an autoimmune reaction, i.e. that the patients reacted against their own white cells. However, this did not fit with the fact that the white cells of the blood donors were killed, but the cells of the recipient remained unharmed. Dausset realized immediately that he had encountered a previously unknown type of genetic variation between people. On the basis of family analyses he could show that the variation was determined by a single genetic system, localized to a single chromosome. It was designated HLA and was found to be analogous with H-2 in the mouse. At this point, the paths of Snell and Dausset converged. Research on mice and humans became mutually complementary. One starts to speak about MHC, or major histocompatibility complex, as a common name for the large sync region and finds that MHC has a closely similar structure in all mammalians. It is also realized that only a fraction of its many components are known: the antibodies of Snell and Dausset have only identified two of its important milestones. It was Benacerraf's work that has brought in a third, very important region, located between the two milestones. Like his colleagues, he also started in a seemingly distant area: the antibody response of guinea pigs and the interplay between different cells within the immune system. He found that the immune response against certain substances varied greatly between different guinea pig strains. This was due to a previously unknown group of genes localized within the MHC complex, designated as immune responsiveness or Ir genes. They were found to influence the ability of different cell types to cooperate within the "immunological orchestra". Some Ir genes help different cell types to collaborate in order to bring about a certain response whereas others suppress reactions that would otherwise get out of control.
The major histocompatibility complex has acquired great medical and biological significance. HLA typing is now indispensable for all forms of tissue and organ transplantation. The rapid practical application of the research results is a direct consequence of the exemplary international cooperation organized by Dausset in the form of the "histocompatibility workshops" where research workers from all countries meet in the laboratory to compare their results, exchange reagents and agree on the nomenclature. Now, the most compatible donor-recipient combinations can be readily identified with the help of the data banks that contain the typing information in a language comprehensible for all.
As a more unexpected byproduct of this activity, a strong relationship was found between certain HLA-types and some diseases, including a rare disease of the spine, juvenile diabetes, multiple sclerosis, a chronic skin disease, etc. The reasons for these associations are not understood, but they further emphasize the great significance of the MHC-region for normal development and function.
Perhaps the most interesting question concerns the role of the MHC system in the normal organism. Why does it exist, why has it been retained with such tenacity and in all its complexity during revolution? Protection from foreign tissue grafts, an artefact of our time, is certainly not the reason. The answer must be sought in the importance of the MHC system for the cooperation between different cells in the organism and for the ability of the immune system to distinguish between normal cells of the body that should not be exposed to an immune rejection, and changed cells that must be eliminated because they threaten the integrity of the organism. Viral infection, cancerous transformation and perhaps even the normal physiological aging of cells can be mentioned as examples. The MHC-system provides an extraordinarily sensitive surveillance system to detect cells with changed membranes; it also provides a mechanism to kill cells that are becoming alienated from their community in one way or another. The rejection of foreign grafts is then merely an unavoidable byproduct.
In the early 1950's, I heard George Snell say that he could count the number of research workers in the world who understood the H-2 system without using all his fingers. The development of this field from an outlandish rejection reaction in inbred mice to the mighty supergene system of today that all immunologists, cancer research workers and many virologists and developmental biologists meet in their daily work is one of the most exciting chapters in the enormous building of modern biology.
Drs. Snell, Dausset and Benacerraf! Starting from three different directions, your long journey has led you, after many adventures, to the same supergene area, the major histocompatibility complex, and through it to this happy event tonight. You have been responsible for turning what at first appeared as an esoteric area of basic research on inbred mice into a major biological system of the greatest significance for the understanding of cell recognition, immune responses and graft rejection. We have the rare esthetic pleasure of seeing a series of fundamental discoveries, coupled with immediate applications in clinical medicine. I am very happy to have the privilege of expressing the congratulations of the Nobel Assembly at the Karolinska Institute and to ask you to receive your Nobel Prize from the hands of His Majesty the King.
From Nobel Lectures, Physiology or Medicine 1971-1980, Editor Jan Lindsten, World Scientific Publishing Co., Singapore, 1992
Copyright © The Nobel Foundation 1980
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